The Immunity Arms Race: Evolution of Antimalarial Drugs

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The Serial Killer

If you were to think of all the diseases in human history which have been catastrophic to civilization, the bubonic plague during the Dark Ages might come to mind. Or instead, perhaps smallpox, a disease estimated to have killed 90% of the indigenous population during American colonization. But, what many may not answer, despite having taken lives time and time again for millenia, persisting even in the modern age, is malaria.

As written in this Nature article about the disease, “Portrait of a serial killer,” estimates once stated that “malaria may have killed half of all the people that ever lived.” While experts now believe the number is not nearly as high, they are confident that malaria can be attributed to at least 3-5% of all human deaths. Throughout history, civilizations have used a variety of natural remedies to treat malaria. Despite lack of understanding behind the disease, humans discovered various plants that seemed to ease the fevers associated with it. For example, the bitter-tasting bark of the cinchona tree, indigenous to the Andes mountains in Peru, was used by the Spanish in the 1600s as a remedy. French chemists Joseph Pelletier and Jean Biename Caventou would eventually isolate the active compound, known as quinine, from cinchona bark in 1820.

However, the origins of malaria and how it spreads remained largely a mystery for many years. The ancient Romans noticed the disease had been linked with swamps, which inspired its name mal’aria (“bad air”). Before the rise of germ theory, people thought that malaria was caused by miasmas, or “evil vapors.” It wasn’t until 1880 when the malaria parasite (Plasmodium falciparum) was discovered, and 1898 when mosquitoes were proved to be the vector for spreading malaria, that scientific understanding began to shift. 

However, it wasn’t before long that quinine became ineffective. During the Vietnam War, soldiers at the Ho Chi Minh trail were being decimated by a new, drug-resistant strain of malaria. Turns out, as malaria treatments evolved, so too did this parasite. 

Finding Modern Solutions in Ancient Texts

In 1969, Tu Youyou, a Chinese scientist, was appointed to lead Project 523, a secret military operation aimed at discovering a treatment for malaria during the Vietnam War. Understanding that malaria is a disease that has afflicted humans for thousands of years, Tu and her team searched through ancient Chinese medical texts for clues. They found over 2,000 remedies with potential antimalarial activity, leading them to test hundreds of plant species on malaria-infected mice. Sweet wormwood plant, otherwise known as qinghao or by its scientific name, Artemisia annua, showed promise. The plant had been traditionally used as a fever reducer. Tu successfully isolated the active component, artemisinin, which displayed remarkable effectiveness in reducing levels of the malaria parasite in blood. For her work, Tu became the first Chinese scientist to win the Nobel Prize in Medicine in 2015.

A Plant's Secret Weapon

Chinese traditional medicine has deep roots in the practice of using plants to treat disease. Like humans, plants have a need to protect themselves against potentially harmful organisms, like parasites, herbivores, and bugs. Not only is artemisinin a natural antimicrobial, its strong, bitter flavor can deter animals from wanting to eat the plant. Though only realized recently thanks to decades of research, plant immune systems have highly sophisticated defense mechanisms. Some pathways share a lot in common with basic principles of human biology, such as signaling biomolecules and complex immune cascades. 

However, many biology students, especially those more focused on the human or medical side of the field, are unaware that plants hold such complex physiology. Dr. Alisa Huffaker is a professor at UC San Diego who researches plant immune systems. She explains that there is actually a term for this, “plant blindness, where we tend to not see plants as living organisms like ourselves.” Her lab is helping to overturn this stereotype by researching plant peptide signals (Peps), which regulate plant defense responses against pathogens and herbivores. 

One biological motif that both plants and humans share in our immune systems are proteins called Toll-like receptors (TLRs). These receptors sit on the surface of our cells and, like a toll gate, inspect incoming molecules before they are allowed to enter the cell. In humans, when TLRs recognize something suspicious, they activate immune cells called interleukins that escalate the response. While plants do not have interleukins, they have Peps. “My peptides are kind of like the plant version of interleukin,” Dr. Huffaker explains. She continues, “The plant is making its own signal that turns on the same things that a microbe signal would to amplify the response.”

Surprisingly, plant defense compounds and their medicinal properties on humans is not entirely a coincidence. “The plant metabolites are not making any of it to affect us, we're not important enough, as far as predators, to do that,” Dr. Huffaker clarifies. “But just by similarities in physiology between insects and us, some of the molecules affect us as well,” she continues. While this might lead many to think that these plants would be harmful to both us and the bugs, these natural insect “toxins” are more common in our lives than many realize, and are usually completely harmless. Examples include caffeine and capsaicin (the molecule that makes peppers spicy), which can kill bugs, but are safe for humans in small amounts. In contrast, “Artemisinin is a really reactive molecule that is like a little bomb, especially for malaria,” Dr. Huffaker explains. Its high reactivity and broad-spectrum antimicrobial capacity make it a great tool for both plants and humans, when used carefully.

Dr. Huffaker emphasizes that there is still so much to investigate in the field of plant immunology and defense mechanisms. She believes there are likely more surprises waiting to be “re-discovered” in ancient medicine. However, unlike the ancient scrolls our ancestors may have been pouring through for patients, research groups today are actively applying modern technology to speed up the process of drug discovery, and malaria is no exception.

Modern Drug Discovery: Building an Ever-Evolving Library

Today, research is being done around the world as scientists continue to develop novel treatments to fight the ever-evolving malaria parasite. Thanks to the power of technology and computers, the screening process has become much more automated. Artificial intelligence has also given rise to many new and exciting possibilities in the drug discovery realm. To learn more about the process of how new treatments for malaria are being developed today, I talked to Dr. Elizabeth Winzeler at UC San Diego. While working at the Stanford Genome Center, she was inspired by a project ongoing at the time to sequence the Plasmodium falciparum genome. Knowing it would soon be fully available, opening the door to countless research possibilities, Dr. Winzeler decided she wanted to take full advantage.

 Her lab uses high-throughput technology to screen massive libraries of chemical compounds for therapeutic potential. She and her team have identified multiple antimalarial compounds now in clinical development. They have had great success in this process, yet it looks very different compared to Tu and her team’s approach in the 60’s.

“We developed with my technician, David Plouffe, an ultra-high throughput, highly predictable assay to identify compounds that were killing malaria parasites,” Dr. Winzeler explains. “We're able to run this on a couple of very, very large chemical libraries, and we found tons of really nice active compounds,” she said.

In the 60’s, Tu and her team had to comb through ancient medical texts themselves to find compounds to screen. Today, thanks to the power of computer databases and the ability to screen thousands of compounds at once with 1536-well plates, the process is much less like finding a “needle in the haystack.” Understanding this, Dr. Winzeler decided in her lab, “let's develop a phenotypic screen that will predict which one of those needles is going to turn into the magic bullet.” She explains, “It's a much more modern approach where you start out with an assay that you think is predictive of what will happen in the body."

Today, there are thousands of research groups and government agencies building curated chemical libraries of compounds for labs like Dr. Winzeler’s to use for drug discovery. As these libraries grow, so is technology’s predictive abilities in identifying potential hits. AI, in particular, is an area that Dr. Winzeler and many of her colleagues are excited about. AI is being actively applied for a process called de novo protein design, or the computational creation of proteins from scratch.

Dr. Winzeler explains, “We are using advances in de novo protein design to look for new therapeutic classes. We're working with Adrian Jinich in the School of Pharmacy, who's been adapting some of the methods that came out of David Baker's lab for making proteins that will bind to a particular receptor.” She continues, “He's de novo engineered a handful of proteins that look really promising.”

Looking to the future, AI will no doubt be a key player in the development of new treatments for diseases like malaria. As researchers work to discover more therapeutic possibilities, they are building upon the shoulders of a vast history of humans passing down found remedies, from ancient medicine to the compound libraries used today. †

Written by Editor and Staff Writer Eleanor Jung (eljung@ucsd.edu)

Works Cited

Arrow, Kenneth J, et al. “A Brief History of Malaria.” Nih.gov, National Academies Press (US), 2004, www.ncbi.nlm.nih.gov/books/NBK215638/.

PBS. “Guns Germs & Steel: Variables. Smallpox | PBS.” Pbs.org, PBS, 2019, www.pbs.org/gunsgermssteel/variables/smallpox.html.

Rogers, Kara. “Tu Youyou | Chinese Scientist and Phytochemist.” Encyclopedia Britannica, 7 Oct. 2015, www.britannica.com/biography/Tu-Youyou.

Whitfield, John. “Portrait of a Serial Killer.” Nature, 3 Oct. 2002, https://doi.org/10.1038/news021001-6.